Statins increase p21 through inhibition of histone deacetylase activity and release of promoter-associated HDAC1/2.
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Lin YC, Lin JH, Chou CW, Chang YF, Yeh SH, Chen CC
Statins increase p21 through inhibition of histone deacetylase activity and release of promoter-associated HDAC1/2.
Cancer Res. 2008 Apr 1;68(7):2375-83. doi: 10.1158/0008-5472.CAN-07-5807.
- PubMed ID
- 18381445 [ View in PubMed]
- Abstract
Statins are 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors broadly used for the control of hypercholesterolemia. Recently, they are reported to have beneficial effects on certain cancers. In this study, we show that statins inhibited the histone deacetylase (HDAC) activity and increased the accumulation of acetylated histone-H3 and the expression of p21(WAF/CIP) in human cancer cells. Computational modeling showed the direct interaction of the carboxylic acid moiety of statins with the catalytic site of HDAC2. In the subsequent enzymatic assay, it was shown that lovastatin inhibited HDAC2 activity competitively with a K(i) value of 31.6 micromol/L. Sp1 but not p53 sites were found to be the statins-responsive element shown by p21 luciferase-promoter assays. DNA affinity protein binding assay and chromatin immunoprecipitation assay showed the dissociation of HDAC1/2 and association of CBP, leading to the histone-H3 acetylation on the Sp1 sites of p21 promoter. In vitro cell proliferation and in vivo tumor growth were both inhibited by statins. These results suggest a novel mechanism for statins through abrogation of the HDAC activity and promoter histone-H3 acetylation to regulate p21 expression. Therefore, statins might serve as novel HDAC inhibitors for cancer therapy and chemoprevention.
DrugBank Data that Cites this Article
- Drugs
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Atorvastatin Histone deacetylase 2 Protein Humans UnknownInhibitorDetails Fluvastatin Histone deacetylase 2 Protein Humans UnknownInhibitorDetails Lovastatin Histone deacetylase 2 Protein Humans NoInhibitorDetails Pravastatin Histone deacetylase 2 Protein Humans UnknownInhibitorDetails Simvastatin Histone deacetylase 2 Protein Humans UnknownInhibitorDetails